HMG-CoA reductase inhibitors (statins), widely used in the reduction of cholesterol, have pleiotropic effects. Based on robust preliminary data, we seek to develop a novel neuro-restorative treatment of ischemic stroke using statins. These agents, when administered one or more days after stroke, enhance brain plasticity and significantly reduce functional deficits after ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate the cellular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo): Aim 1 will measure the effects of different doses of statins (simvastatin or atorvastatin) on functional recovery and brain plasticity in old and young adult mice after stroke. The hypothesis to be tested is that treatment of stroke with statins, initiated at one day after stroke onset, improves neurological functional recovery and enhances brain plasticity. Aim 2 will measure the temporal profile and induction of angiogenesis in ischemic brain treated with statins, the relationship between statin-induced angiogenesis and functional recovery, and potential downstream molecular targets, including synaptic protein expression and the localization of progenitor cells at sites of angiogenesis in ischemic brain. The contribution of VEGF, VEGFR2 and eNOS to statin-induced brain plasticity will be examined by using a specific antibody to VEGFR2 and eNOS knockout mice subjected to stroke and treated with statins, respectively. The underlying hypotheses are that: statins foster functional recovery after stroke by promoting the expression and activation of VEGF/VEGFR2 and eNOS within cerebral tissue; VEGF/VEGFR2 and eNOS instigate brain plasticity via the induction of angiogenesis and provide a microenvironment in brain to further enhance synaptic protein expression and presence of progenitor cells, which augment functional recovery after statin treatment. This study provides a new and highly effective way to treat stroke and may permit translation our finding of restorative therapeutic benefit of statin in experimental stroke to the patient.